Medical diagnostic imaging has evolved as an important non-invasive tool for medical diagnosis. Nuclear magnetic resonance imaging (“MRI”) and computerized tomography (“CT”) are two of the most widely used imaging methods. MRI generally relies on the relaxation properties of excited hydrogen nuclei in water. When the tissues or organs to be imaged are placed in a powerful, uniform magnetic field, the spins of the hydrogen protons within the tissues or organs align along the axis of the magnetic field.
The tissue is then briefly exposed to pulses of electromagnetic energy (RF pulse) in a plane perpendicular to the magnetic field, causing some of the magnetically aligned hydrogen nuclei to assume a temporary non-aligned high-energy state. As the high-energy nuclei relax and realign, they emit energy which is recorded to provide information about their environment. The realignment with the magnetic field is termed longitudinal relaxation and the time in milliseconds required for a certain percentage of the tissue nuclei to realign is termed “Time 1” or T1. This is the basis of T1-weighted imaging. T2-weighted imaging relies upon local dephasing of spins following the application of the transverse energy pulse; the transverse relaxation time is termed “Time 2” or T2. Both T1- and T2-weighted images are acquired for most medical examinations.
MRI takes advantage of the fact that water relaxation characteristics vary from tissue to tissue, and this tissue-dependent relaxation effect provides image contrast, which in turn allows the identification of various distinct tissue types. In order to create an image, spatial information must be recorded along with the received tissue relaxation information. A computer applies an inverse Fourier transform to this information so that it is converted into real space to obtain the desired image. This produces detailed anatomical information of the tissues or organs under inspection.
A modern MRI scanner will include a complex library of RF pulse sequences, each of which is optimized to provide image contrast based on the chemical sensitivity of MRI. The amount of time between successive pulse sequences is commonly referred to as the repetition time (TR). Another measurement used to characterize the RF pulse sequences is the echo time (TE). By varying these two parameters, the MRI scanner can produce T1-emphasized images or T2-emphasized images. A relatively short TR, on the order of a hundred to several hundred milliseconds, when combined with a relatively short TE, on the order of ten milliseconds, typically will produce T1-emphasized image. A relatively longer TR, on the order of a thousand milliseconds or longer, when combined with a relatively longer TE, on the order of ten to a hundred milliseconds, will produce a T2-emphasized image.
In order to increase the signal-to-noise ratio (“SNR”), a typical MRI scan is repeated at a constant rate for a predetermined number of times and the data is subsequently averaged. The signal amplitude recorded for any given scan is proportional to the number of spins that have decayed back to equilibrium in the time period between successive scans. Thus, regions with rapidly relaxing spins (i.e. those regions comprising spins having short T1 values) will recover all of their signal amplitude between successive scans. The measured intensities of the regions with long T2 and short T1 will reflect the spin density, which correlates with the region's water content. Regions with long T1 values, as compared to the time between scans, will progressively lose signal until a steady state condition is reached. At the steady state condition, the signal will be indistinguishable from background noise.
Although MRI can be performed without the administration of contrast agents, the ability to enhance the visualization of internal tissues and organs has resulted in their widespread use. Paramagnetic contrast agents effect a change in the relaxation characteristics of protons. In other words they can serve to modulate T1 and/or T2 values. This is particularly useful for imaging adjacent soft tissues, which may be histologically different but magnetically similar. An MRI scan obtained without the use of a contrast agent may not substantially differentiate between such adjacent soft tissues. If a contrast agent is localized in one of the two adjacent tissues, however, the imaging contrast can be substantially improved.
When designing or selecting contrast agents, two fundamental properties must be considered: a) biocompatibility, and b) proton relaxation enhancement. Biocompatibility is influenced by several factors including toxicity, stability (thermodynamic and kinetic), pharmacokinetics and biodistribution. Proton relaxation enhancement and relaxivity is chiefly governed by the metal employed in the agent, the rotational correlation times and the accessibility of the metal to surrounding water molecules, which permits the rapid exchange of metal-associated water molecules with the bulk solvent. The contrast agents most widely used are based upon ligand-stabilized gadolinium ions. Commercially available examples of these include Omniscan (gadodiamide), which is commercially available from Amersham Health, and ProHance (gadoteridol), which is commercially available from Bracco Diagnostics. Another widely used contrast agent is based upon sugar-coated iron-oxide (magnetite, Fe3O4) nanoparticles. This is commercially available from Mallinckrodt as GastroMARK (ferumoxsil). Another iron-based contrast agent is available from Berlex as Feridex (ferumoxides).